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Stroke remained the second leading cause of death globally in 2019. The antiplatelet drug clopidogrel is used to keep blood clots from forming in people who have experienced a stroke. Although most people find clopidogrel to be safe and beneficial, there is inevitably a range in how each patient responds. The review covers about Clopidogrel resistance in stroke patients, their risk factors and the methods to identify it. Clopidogrel resistance is characterized as the drug's inability to prevent the target enzyme from acting. The prognosis of patients with ischemic stroke and the responsiveness to clopidogrel are significantly impacted by the various genetic polymorphism CYP2C19 genotypes. The two primary mutant alleles, CYP2C19 *2 and CYP2C19 *3, have been found to be the most prevalent genotypes. Better mRS scores six months after treatment showed a higher response rate in patients without these CYP2C19 variant alleles. Other factors are drug-drug interaction (proton pump inhibitors), demographics (age, sex, social history), comorbid conditions, etc. Blood samples for testing platelet reactivity were drawn one month after discharge from a peripheral blood sample. Several methods are used to identify the clopidogrel resistance. Some of them are ADP-Induced platelet aggregation, Platelet Reactivity Index VASP, Verify Now Assay, TEG Analyzer, Plasma microRNA-223. Drugs that are not prodrugs and whose metabolism is not dependent upon CYP2C19 can be selected as a superior alternative in case of CR. Ticagrelor is one such effective substitute. Proton pump inhibitors and clopidogrel should only be used concurrently in patients with reliable clinical indications. Keywords: Clopidogrel resistance, genetic polymorphism, high platelet reactivity, ischemic stroke, platelet reactivity, ticagrelor, Author(s): S Lavanya (corresponding author) [1]; Dhanashri Babu [1]; D Dheepthi [1]; E Dhinakar [1]; G Vivekanandh [1] Introduction Stroke is described as 'rapidly developing clinical signs of focal (or [...]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan, China (1). SARS-CoV-2 has since spread to [approximately equal to]185 countries and infected [approximately equal to]6 million [...]

Emerging artemisinin resistance to Plasmodium falciparum endangers malaria control worldwide. Currently, the resistance epicenter is the greater Mekong subregion in Southeast Asia (1). In sub-Saharan Africa, where illnesses and deaths [...]

UL18 is a human CMV (HCMV) MHC class I (MHCI) homolog that efficiently inhibits leukocyte immunoglobulin-like receptor subfamily B member 1 [(LILRB1).sup.+] NK cells. We found an association of LILRB1 polymorphisms in the regulatory regions and ligand-binding domains with control of HCMV in transplant patients. Naturally occurring LILRB1 variants expressed in model NK cells showed functional differences with UL18 and classical MHCI, but not with HLA-G. The altered functional recognition was recapitulated in binding assays with the binding domains of LILRB1. Each of 4 nonsynonymous substitutions in the first 2 LILRB1 immunoglobulin domains contributed to binding with UL18, classical MHCI, and HLA-G. One of the polymorphisms controlled addition of an N-linked glycan, and that mutation of the glycosylation site altered binding to all ligands tested, including enhancing binding to UL18. Together, these findings indicate that specific LILRB1 alleles that allow for superior immune evasion by HCMV are restricted by mutations that limit LILRB1 expression selectively on NK cells. The polymorphisms also maintained an appropriate interaction with HLA-G, fitting with a principal role of LILRB1 in fetal tolerance., Introduction NK cells play a critical role during the early stages of human CMV (HCMV) infection, and the presence of HCMV alters the NK compartment (1, 2). The alterations include [...]

Background/Objectives: The objective of the study was to assess the role of variations in serum folate, vitamin B12, homocysteine and the presence of genetic polymorphisms as risk factors for congenital heart disease (CHD) in children. Subjects/Methods: A total of 32 children with CHD, and their mothers and 32 normal children and their mothers formed the study and control groups, respectively. Serum folate, vitamin B12 and homocysteine as well as genetic polymorphisms MTHFR C677[right arrow]T, MTHFR A1298[right arrow]C, MTR A2756[right arrow]G and MTRR A66[right arrow]G were assessed. Results: Low serum folate and genetic polymorphisms MTHFR C677[right arrow]T and MTRR A66[right arrow]G among children and their mothers and high homocysteine among mothers were noted as risk factors for CHD (P Conclusions: Low serum folate, high homocysteine and presence of selected genetic polymorphisms among children and their mothers were noted as risk factors for CHD. Nutrient-gene interaction being a modifiable risk factor, the study recommends the use of peri-conceptional folate supplementation with vitamin B12 sufficiency for primary prevention of CHD., Author(s): K E Elizabeth [sup.1] , S L Praveen [sup.1] , N R Preethi [sup.2] , V T Jissa [sup.2] , M R Pillai [sup.2] Author Affiliations: (1) Department of [...]

Drug-resistant tuberculosis (TB) poses a significant threat to global health, with an estimated 480,000 new cases of multidrug-resistant tuberculosis (MDR TB) in 2014; 10% of these cases were classified as [...]

Background: Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume. Methods: Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) x PTSD severity interaction and its association with hippocampal volume. Results: We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype x PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. Limitations: The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. Conclusion: Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD., Introduction Memory disturbances manifested in the form of intrusive trauma memories, flashbacks and deficits in episodic memory are among the hallmark symptoms of posttraumatic stress disorder (PTSD). (1) These memory [...]

We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure-associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42's role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9-mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic c/s-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies., Introduction Although hypertension is a major risk factor for stroke, myocardial infarction, and kidney failure (1), surprisingly little is known about the genetic mechanisms that contribute to its development. GWAS [...]

Background: Multivariable baseline factor analysis across CAB+RPV phase 3 studies recently showed that HIV-1 subtypes A6/A1, characterized by the L74I integrase (IN) polymorphism, and presence of RPV resistance-associated mutations (RAM), [...]

Byline: Hamidreza. Jahanbani-Ardakani, Fereshteh. Alsahebfosoul, Masoud. Etemadifar, Seyed-Hossein. Abtahi Background: Multiple sclerosis (MS) is a chronic demyelinating disorder of central nervous system. Although the definite pathogenesis of MS has not [...]

Background: The rapidly increasing dissemination of carbapenem-resistant Enterobacteriaceae (CRE) in both humans and animals poses a global threat to public health. However, the transmission of CRE between humans and animals has not yet been well studied. Objectives: We investigated the prevalence, risk factors, and drivers of CRE transmission between humans and their backyard animals in rural China. Methods: We conducted a comprehensive sampling strategy in 12 villages in Shandong, China. Using the household [residents and their backyard animals (farm and companion animals)] as a single surveillance unit, we assessed the prevalence of CRE at the household level and examined the factors associated with CRE carriage through a detailed questionnaire. Genetic relationships among human- and animal-derived CRE were assessed using whole-genome sequencing-based molecular methods. Results: A total of 88 New Delhi metallo-[beta]-lactamases-type carbapenem-resistant Escherichia coli (NDM-EC), including 17 from humans, 44 from pigs, 12 from chickens, 1 from cattle, and 2 from dogs, were isolated from 65 of the 746 households examined. The remaining 12 NDM-EC were from flies in the immediate backyard environment. The NDM-EC colonization in households was significantly associated with a) the number of species of backyard animals raised/kept in the same household, and b) the use of human and/or animal feces as fertilizer. Discriminant analysis of principal components (DAPC) revealed that a large proportion of the core genomes of the NDM-EC belonged to strains from hosts other than their own, and several human isolates shared closely related core single-nucleotide polymorphisms and [bla.sub.NDM] genetic contexts with isolates from backyard animals. Conclusions: To our knowledge, we are the first to report evidence of direct transmission of NDM-EC between humans and animals. Given the rise of NDM-EC in community and hospital infections, combating NDM-EC transmission in backyard farm systems is needed. https://doi.org/10.1289/EHP5251, Introduction Carbapenems, particularly imipenem, meropenem, and ertapenem, play a vital role in the treatment of human clinical infections caused by multidrug-resistant (MDR) Gram-negative bacteria (Nordmann et al. 2012). Carbapenems are [...]

Byline: Beuy. Joob, Viroj. Wiwanitkit Sir, Cyclooxygenase-2 (COX-2) is an important enzyme for the synthesis of prostaglandins bioprocess. COX-2 plays a role in inflammation response. There are many reports regarding [...]

Azole antifungal drugs are the first line of therapy against Aspergillus fumigatus, a common etiologic agent of aspergillosis. These drugs are used as empirical prophylaxis and as targeted therapy for [...]

Byline: Suzan. Pektas, Gursoy. Dogan, Tuba. Edgunlu, Sevim. Karakas-Celik, Esra. Ermis, Nilgun. Tekin Background: Psoriasis is a chronic inflammatory skin disorder, which is characterized by a heightened immunological response. Although [...]

Byline: Iman. Seleit, Ola. Bakry, Eman. El Gayed, Abd. Gawad D Background: Alopecia areata (AA) is a common dermatologic disease with suspected autoimmune etiology. Tumor necrosis factor superfamily member 6 [...]

According to the World Health Organization (WHO) Global Burden of Disease Project, alcohol accounts for approximately 3.2 percent of all deaths per year worldwide (corresponding to 1.8 million people) and [...]

Background: The filaggrin protein is important for skin barrier structure and function. Loss-of-function (null) mutations in the filaggrin gene FLG may increase dermal absorption of chemicals. Objective: The objective of the study was to clarify if dermal absorption of chemicals differs depending on FLG genotype. Method: We performed a quantitative real-time polymerase chain reaction (qPCR)-based genetic screen for loss-of-function mutations (FLG null) in 432 volunteers from the general population in southern Sweden and identified 28 FLG null carriers. In a dermal exposure experiment, we exposed 23 FLG null and 31 wild-type (wt) carriers to three organic compounds common in the environment: the polycyclic aromatic hydrocarbon pyrene, the pesticide pyrimethanil, and the ultraviolet-light absorber oxybenzone. We then used liquid-chromatography mass-spectrometry to measure the concentrations of these chemicals or their metabolites in the subjects' urine over 48 h following exposure. Furthermore, we used long-range PCR to measure FLG repeat copy number variants (CNV), and we performed population toxicokinetic analysis. Results: Lag times for the uptake and dermal absorption rate of the chemicals differed significantly between FLG null and wt carriers with low (20-22 repeats) and high FLG CNV (23-24 repeats). We found a dose-dependent effect on chemical absorption with increasing lag times by increasing CNV for both pyrimethanil and pyrene, and decreasing area under the urinary excretion rate curve [(AUC.sub.(0-40hj)]) with increasing CNV for pyrimethanil. FLG null carriers excreted 18% and 110% more metabolite (estimated by [AUC.sub.(0-40hj)]) for pyrimethanil than wt carriers with low and high CNV, respectively. Conclusion: We conclude that FLG genotype influences the dermal absorption of some common chemicals. Overall, FLG null carriers were the most susceptible, with the shortest lag time and highest rate constants for skin absorption, and higher fractions of the applied dose excreted. Furthermore, our results indicate that low FLG CNV resulted in increased dermal absorption of chemicals. https://doi.org/10.1289/EHP7310, Introduction Exposure to chemicals on the skin can cause skin diseases, such as irritant and allergic contact dermatitis, urticaria, and skin cancer (Anderson and Meade 2014). Dermal exposure is also [...]

Disorders of water balance are among the most common and morbid of the electrolyte disturbances, and are reflected clinically as abnormalities in the serum sodium concentration. The transient receptor potential vanilloid 4 (TRPV4) channel is postulated to comprise an element of the central tonicity-sensing mechanism in the mammalian hypothalamus, and is activated by hypotonic stress in vitro. A nonsynonymous polymorphism in the TRPV4 gene gives rise to a Pro-to-Ser substitution at residue 19. We show that this polymorphism is significantly associated with serum sodium concentration and with hyponatremia (serum sodium concentration [less than or equal to]135 mEq/L) in 2 non-Hispanic Caucasian male populations; in addition, mean serum sodium concentration is lower among subjects with the [TRPV4.sup.P19S] allele relative to the wild-type allele. Subjects with the minor allele were 2.4-6.4 times as likely to exhibit hyponatremia as subjects without the minor allele (after inclusion of key covariates). Consistent with these observations, a human TRPV4 channel mutated to incorporate the [TRPV4.sup.P19S] polymorphism showed diminished response to hypotonic stress (relative to the wild-type channel) and to the osmotransducing lipid epoxyeicosatrienoic acid in heterologous expression studies. These data suggest that this polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis. association study | osmoregulation | sodium | transient receptor potential | cell volume regulation

Idd3 is one of many gene regions that affect the development of type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse. Idd3 has been localized to a 650-kb region on chromosome 3 containing the IL-2 gene. Exon 1 of the IL-2 gene is polymorphic between the susceptible NOD and the protective C57BL/6 (B6) alleles, causing multiple amino acid changes that have been proposed to be responsible for the differing glycosylation status. To address whether this coding polymorphism recapitulates the disease suppression mediated by the B6 Idd3 allele, we generated knockin mice in which exon 1 of the B6 IL-2 allele replaces the homologous region in the NOD allele. We generated these mice by targeting the NOD allele of NOD/129 [F.sub.1] ES cells. IL-2 protein from the knockin mice showed the glycosylation pattern of the B6 IL-2 isoform, confirming that the amino acid differences encoded within exon 1 affect the glycosylation of the IL-2 protein. However, unlike NOD.B6 Idd3 congenic mice, the knockin mice were not protected from T1D. Furthermore, the difference in amino acid sequence in the IL-2 protein did not affect the level of expression of IL-2. This approach provides a general method for the determination of a functional role of a given genomic sequence in a disease process. Further, our result demonstrates that the variants in exon 1 of the IL-2 gene are not responsible for T1D suppression in NOD.B6 Idd3 mice, thereby supporting the hypothesis that variants in the regulatory region affecting expression levels are causative. Idd3 | NOD ES cells | flanking gene problem

Background: The relation between dietary fat, blood lipids, plasma factor VII coagulant activity (FVllc) and risk of coronary heart disease (CHD) according to the R353Q polymorphism in the factor VII gene was assessed. Methods: Cross-sectional study of 15 073 individuals participating in the European Prospective Investigation of Cancer (EPIC) Norfolk, 7433 of which had FVllc available. Nested case-control study of 985 CHD cases and 2009 matched controls. Results: FVllc was significantly associated with total fat intake in females, especially in the RR homozygotes (standardized [beta] = 0.24; 95% confidence interval (95% CI) 0.08-0.40; P Conclusion: These results show a strong association between dietary fat intake and FVllc in women, and between serum triacylglycerol and cholesterol and FVllc levels in both genders. The R353Q genotype only marginally affected modulation of FVllc by dietary fat. The association between triacylglycerol and FVllc was significantly stronger in males carrying the Q allele than in those with the RR genotype. doi:10.1038/ejcn.2008.28; published online 9 April 2008 Keywords: coronary heart disease; diet; factor Vllc; R353Q polymorphism; serum lipids, Introduction Fat intake, especially saturated fatty acid (SFA) intake, is an important determinant of coronary heart disease (CHD) risk, either through its role in raising total low-density lipoprotein (LDL) cholesterol [...]

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) may increase breast cancer risk, and the association may be modified by inherited differences in deactivation of PAH intermediates by glutathione S-transferases (GSTs). Few breast [...]

Mutations and polymorphisms in complement genes have been linked with numerous rare and prevalent disorders, implicating dysregulation of complement in pathogenesis. The 3 common alleles of factor B (fB) encode Arg ([fB.sub.32R]), Gln ([fB.sub.32Q]), or Trp ([fB.sub.32w]) at position 32 in the Ba domain. The [fB.sub.32Q] allele is protective for age-related macular degeneration, the commonest cause of blindness in developed countries. Factor B variants were purified from plasma of homozygous individuals and were tested in hemolysis assays. The protective variant [fB.sub.32Q] had decreased activity compared with [fB.sub.32R]. Biacore comparison revealed markedly different proenzyme formation; [fB.sub.32R] bound C3b with 4-fold higher affinity, and formation of activated convertase was enhanced. Binding and functional differences were confirmed with recombinant [fB.sub.32R] and [fB.sub.32Q]; an intermediate affinity was revealed for [fB.sub.32w]. To confirm contribution of Ba to binding, affinity of Ba for C3b was determined. Ba-[fB.sub.32R] had 3-fold higher affinity compared with Ba-[fB.sub.32Q]. We demonstrate that the disease-protective effect of [fB.sub.32Q] is consequent on decreased potential to form convertase and amplify complement activation. Knowledge of the functional consequences of polymorphisms in complement activators and regulators will aid disease prediction and inform targeting of diagnostics and therapeutics. alternative pathway | AMD

The HGF gene is transcriptionally silenced in normal differentiated breast epithelial cells, but its repression fails to occur in mammary carcinoma tissues and cell lines. The molecular mechanisms underpinning aberrant HGF expression in breast cancer cells are unknown. Here we report the discovery of a DNA element located 750 bp upstream from the transcription start site in the human HGF promoter that acts as a transcriptional repressor and is a target of deletion mutagenesis in human breast cancer cells and tissues. This HGF promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which we have termed "deoxyadenosine tract element" (DATE). Functional studies revealed that truncation mutations within DATE have profound local and global effects on the HGF promoter region by modulating chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter in human breast carcinoma cell lines. We found that 51% of African Americans and 15% of individuals of mixed European descent with breast cancer harbor a truncated DATE variant (25As or fewer) in their breast tumors and that the truncated allele is associated with cancer incidence and aberrant HGF expression. Notably, breast cancer patients with the truncated DATE variant are substantially younger than those with a wild-type genotype. We also suggest that DATE may be used as a potential genetic marker to identify individuals with a higher risk of developing breast cancer., Introduction Acquisition of an autocrine growth-stimulating circuit is a hallmark of cancer cells (1). HGF is an important paracrine mediator of mesenchymal-epithelial interaction, instructing epithelial cells to undergo processes such [...]

Prior work has shown that heterozygosity G/C of single nucleotide polymorphism (SNP rs2910164) within the precursor of microRNA-146a predisposes to PTC (odds ratio = 1.62, P = 0.000007) although the mechanism was unclear. Here, we show that GC heterozygotes differ from both GG and CC homozygotes by producing 3 mature microRNAs: 1 from the leading strand (miR-146a), and 2 from the passenger strand (miR-146a*G and miR-146a*C), each with its distinct set of target genes. TaqMan analysis of paired tumor/ normal samples revealed 1.5- to 2.6-fold overexpression of polymorphic miR-146a* in 7 of 8 tumors compared with the unaffected part of the same gland. The microarray data showed that widely different transcriptomes occurred in the tumors and in unaffected parts of the thyroid from GC and GG patients. The modulated genes are mainly involved in regulation of apoptosis leading to exaggerated DNA-damage response in heterozygotes potentially explaining the predisposition to cancer. We propose that contrary to previously held views transcripts from the passenger strand of miRs can profoundly affect the downstream effects. Heterozygosity for polymorphisms within the premiR sequence can cause epistasis through the production of additional mature miRs. We propose that mature miRs from the passenger strand may regulate many genetic processes. papillary thyroid carcinoma | polymorphism | PTC

BACKGROUND: The frequency of chromosomal aberrations (CA) in peripheral blood lymphocytes of healthy individuals has been associated with cancer risk. It is presently unclear whether this association is influenced by [...]

Mood disorders cause much suffering and are the single greatest cause of lost productivity worldwide. Although multiple medications, along with behavioral therapies, have proven effective for some individuals, millions of people lack an effective therapeutic option. A common serotonin (5-HT) transporter (5-HTT/SERT, SLC6A4) polymorphism is believed to confer lower 5-HTT expression in vivo and elevates risk for multiple mood disorders including anxiety, alcoholism, and major depression. Importantly, this variant is also associated with reduced responsiveness to selective 5-HT reuptake inhibitor antidepressants. We hypothesized that a reduced antidepressant response in individuals with a constitutive reduction in 5-HTT expression could arise because of the compensatory expression of other genes that inactivate 5-HT in the brain. A functionally upregulated alternate transporter for 5-HT may prevent extracellular 5-HT from rising to levels sufficiently high enough to trigger the adaptive neurochemical events necessary for therapeutic benefit. Here we demonstrate that expression of the organic cation transporter type 3 (OCT3, SLC22A3), which also transports 5-HT, is upregulated in the brains of mice with constitutively reduced 5-HTT expression. Moreover, the OCT blocker decynium-22 diminishes 5-HT clearance and exerts antidepressantlike effects in these mice but not in WT animals. OCT3 may be an important transporter mediating serotonergic signaling when 5-HTT expression or function is compromised. 5HTTLPR | antidepressant | polymorphism | hippocampus | chronamperometry

BACKGROUND: Disturbances of heart rate variability (HRV) may represent one pathway by which second-hand smoke (SHS) and air pollutants affect cardiovascular morbidity and mortality. The mechanisms are poorly understood. OBJECTIVES: [...]

Perilipin (PLIN) is the major protein surrounding lipid droplets in adipocytes and regulates adipocyte metabolism by modulating the interaction between lipases and triacylglycerol stores. Associations between PLIN gene polymorphisms and obesity risk have been described, but interactions with dietary macronutrients require further attention. We examined whether dietary macronutrients (e.g. carbohydrates and fats) modulated the associations of the common PLIN 11482G > A (rs894160) single nucleotide polymorphism with obesity. We studied a population-based sample of Caribbean-origin Hispanics (n = 920, aged 45-74 y) living in the Boston area. Obesity measures (waist and hip circumference, BMI) did not differ between GG subjects and carriers of the A allele (GA and AA). In multivariate linear regression models, we found a significant interaction between complex carbohydrate intake as a continuous variable and PLIN 11482 G > A genotype for waist circumference (P = 0.002). By dichotomizing complex carbohydrate intake, we found significantly different effects across PLIN 11482G > A genotypes. When complex carbohydrate intake was < 144 g/d, waist circumference was larger in PLIN 11482G > A carriers (P = 0.024). Conversely, when complex carbohydrate intake was [greater than or equal to] 144 g/d, waist and hip circumferences were less in PLIN 11482G > A carriers (P < 0.05). These interactions were not found for simple sugars or total carbohydrates. We identified a significant gene-diet interaction associated with obesity at the PLIN locus. In subjects with higher complex carbohydrate intake, the minor allele was protective against obesity, whereas in subjects with lower carbohydrate intake, the minor allele was associated with increased obesity. These interactions may be relevant to dietary management of obesity.

Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. Interindividual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. Common single nucleotide polymorphisms (SNPs) at the BCL11A and HBS1L-MYB loci have been implicated previously in HbF level variation in nonanemic European populations. We recently demonstrated an association between a BCL11A SNP and HbF levels in one SCD cohort [Uda M, et al. (2008) Proc Natl Acad Sci USA 105:1620-1625]. Here, we genotyped additional BCL11A SNPs, HBS1L-MYB SNPs, and an SNP upstream of [sup.G][gamma]-globin (HBG2; the Xmnl polymorphism), in two independent SCD cohorts: the African American Cooperative Study of Sickle Cell Disease (CSSCD) and an SCD cohort from Brazil. We studied the effect of these SNPs on HbF levels and on a measure of SCD-related morbidity (pain crisis rate). We strongly replicated the association between these SNPs and HbF level variation (in the CSSCD, P values range from 0.04 to 2 x [10.sup.-42]). Together, common SNPs at the BCL11A, HBS1L-MYB, and [beta]-globin (HBB) loci account for >20% of the variation in HbF levels in SCD patients. We also have shown that HbF-associated SNPs associate with pain crisis rate in SCD patients. These results provide a clear example of inherited common sequence variants modifying the severity of a monogenic disease. genetic modifier | single nucleotide polymorphism | globin gene regulation

Objective: The aim of this study was to evaluate the role of the C677T-MTHFR (methylenetetrahydrofolate reductase)-polymorphism (CC, CT and TT) for vascular complications in liver transplant recipients. Design: Retrospective study. [...]

Adenosine diphosphate (ADP)-ribosylation factor-like tumour suppressor gene 1(ARLTS1) might be associated with an increased risk of several types of familial cancers. However, previous studies have shown that cancer susceptibility is not completely consistent with ARLTS1 polymorphisms, and the precise mechanism remains unknown. Therefore, we conducted a meta-analysis of case-control studies by searching the PubMed, Embase, OVID, Science Direct and Chinese National Knowledge Infrastructure (CNKI) databases. In total, 12 studies met the inclusion criteria and were included in this meta-analysis. Statistical analyses were performed using STATA 11.0 software. Overall, the Cys148Arg T > C variant significantly increased cancer risk (CC vs. TT: OR = 1.27, 95% CI = 1.15-1.41, P < 0.05). The stratification indicated that the Cys148Arg variant is significantly associated with sporadic cancer (CC vs. TT: OR = 1.36, 95% CI = 1.18-1.55) and familial cancer (CC vs. TT: OR = 1.26, 95% CI = 1.12-1.43). Trp149Stop, Pro131Leu, Ser99Ser and Leu132Leu were not correlated with cancer susceptibility. Based on these results, we demonstrated that the ARLTS1 Cys148Arg polymorphism is associated with an increased risk of sporadic cancer and familial cancer, and there were no associations between the other four SNPs (i.e., Trp149Stop, Pro131Leu, Ser99Ser and Leu132Leu) and cancer risk. Keywords: ARLTS1, Gene polymorphism, Cancer risk, Familial cancer, Meta-analysis, Author(s): Yan Jiang[sup.1] , Chen-Yang Zhao[sup.1] , Li-Chun Cheng[sup.1] , Bing Xu[sup.1] and Hui-Yi Lv[sup.1] Background Adenosine diphosphate (ADP)-ribosylation factor-like tumour suppressor gene 1 (ARLTS1 ), which is also known [...]

Background&sol;Objectives: Homocysteine (Hcy) is a key intermediate in methionine metabolism. A high plasma concentration of Hcy is an independent risk factor for cardiovascular diseases among other determinants. In this study, we aimed to investigate the interactions between methylenetetrahydrofolate reductase enzyme gene (MTHFR) polymorphisms and lifestyle variables (smoking, alcohol intake and physical activity) on Hcy concentrations in a young Brazilian population. Subjects&sol;Methods: The study population comprised 3803 individuals from the Pelotas Birth Cohort, aged 22-23 years. Allelic discrimination assays and chemiluminescence immunoassays were performed for genotyping and serum Hcy measurements, respectively. Linear regression models were used to explore the effect of gene-lifestyle interactions on Hcy concentrations. Results: Men carrying the MTHFR 677TT genotype, who were also smokers and drinkers ([succeeds/equal to]15 g of alcohol per day), had the highest concentration of Hcy (P-value for the interaction [less than] 0.001 for smoking and 0.002 for alcohol intake). In contrast, high folate concentrations attenuated the effects of the MTHFR C677T genotype on serum Hcy concentrations (P-value for interaction [less than] 0.001). Also, among males, blood folate concentration was the only lifestyle variable able to modify the influence of MTHFR A1298C genotypes on Hcy concentrations (P-value for the interaction [less than] 0.001). There was no strong evidence of an interaction between the MTHFR genotypes and the lifestyle variables in women. Conclusions: In summary, our study demonstrates a sex difference in Hcy concentrations among Brazilian young adults regarding MTHFR C677T-lifestyle interactions that are worsened under conditions of low blood folate. Identification of potentially modifiable factors related to an increase in homocysteine in young adults, especially in those who are genetically susceptible, is important to prevent negative health consequences in the future. European Journal of Clinical Nutrition (2017) 71, 259-266; doi: 10.1038/ejcn.2016.193; published online 19 October 2016, Author(s): I O Oliveira [1]; L P Silva [2]; M C Borges [3]; O M Cruz [2]; J W Tessmann [2]; J V S Motta [3]; F K Seixas [2]; [...]

Background: Low-function alleles of the serotonin transporter promoter polymorphism (5HTTLPR) have been linked to various psychopathological entities, especially in individuals exposed to prior stressors. In women with bulimic syndromes, we [...]